1. PRENATAL DIAGNOSIS
Prenat Diagn 2011; 31: 3–6.
Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/pd.2685
EDITORIAL
A model for a new pyramid of prenatal care based
on the 11 to 13 weeks’ assessment
Kypros H. Nicolaides1,2 *
1
Harris Birthright Research Centre of Fetal Medicine, King’s College Hospital, London, UK
2
Department of Fetal Medicine, University College Hospital, London, UK
One century ago it was recognized that with the methods
and material at our disposal we were not making all
the progress possible toward solving many problems
of prenatal diagnosis and treatment (Ballantyne, 1901,
1921). In order to achieve these objectives it was urged
that a new means of investigation should be undertaken
which had not yet been tried, at least not yet attempted
on a large scale and in a systematic fashion. This led
to the introduction of prenatal care which constituted a
major advance in the care of pregnant women and played
a pivotal role in the substantial reduction in maternal and Figure 1—Pyramid of prenatal care: past (left) and future (right)
perinatal mortality achieved during the last century.
In 1929, the Ministry of Health in the UK issued FETAL ANEUPLOIDIES
a Memorandum on Antenatal Clinics recommending
that women should first be seen at 16 weeks, then at We have learnt that about 90% of fetuses with major ane-
24 and 28 weeks, fortnightly thereafter until 36 weeks uploidies can be identified by a combination of maternal
and then weekly until delivery (Figure 1) (Ministry of age, fetal nuchal translucency (NT) thickness and mater-
Health Report, 1929). No explicit rationale was offered nal serum-free ß-hCG and PAPP-A at 11 to 13 weeks
for either the timing or clinical content of visits, yet (Nicolaides, 2011). Improvement in the performance of
these guidelines established the pattern of prenatal care first-trimester screening can be achieved by first carry-
to be followed throughout the world until now. The ing out the biochemical test at 9 to 10 weeks and the
high concentration of visits in the late third trimester ultrasound scan at 12 weeks and second, inclusion in
implies that most complications occur toward the end the ultrasound examination assessment of the nasal bone
of pregnancy and most adverse outcomes cannot be and flow in the ductus venosus, hepatic artery and across
predicted from the first trimester. However, is this really the tricuspid valve. A similar performance of screening
the case? Scientific advances in the last 20 years have can be achieved by examining the additional ultrasound
raised the hope that many pregnancy complications are markers in all cases and by a contingent policy in which
potentially detectable from at least as early as the 12th first-stage combined screening classifies the patients as
week of gestation. It has become apparent that most high-, intermediate- and low-risk and the new markers
major aneuploidies can be identified at 11 to 13 weeks’ are examined only in the intermediate-risk group which
gestation by a combination of maternal characteristics, is then reclassified as low- or high-risk.
ultrasound findings and biochemical testing of maternal
blood. It is also becoming increasingly apparent that
an integrated first hospital visit at 11 to 13 weeks FETAL STRUCTURAL ABNORMALITIES
combining data from maternal characteristics and history
with findings of biophysical and biochemical tests can We have learnt that at the 11 to 13 weeks’ scan it
define the patient-specific risk for a wide spectrum is possible to diagnose or suspect the presence of
of pregnancy complications, including miscarriage and most major abnormalities, which are either lethal or
fetal death, preterm delivery, preeclampsia, gestational associated with severe handicap, so that the parents
diabetes, fetal growth restriction and macrosomia. can have the option of earlier and safer pregnancy
termination. Major fetal abnormalities fall into essen-
tially three groups in relation to whether they can be
*Correspondence to: Prof. Kypros H. Nicolaides, Harris Birthright
Research Centre for Fetal Medicine, King’s College Hospital, detected at the 11 to 13 weeks’ scan (Syngelaki et al.,
Denmark Hill, London SE5 9RS, UK. 2011): first, those which are always detectable abnor-
E-mail: kypros@fetalmedicine.com malities, including body stalk anomaly, anencephaly,
Copyright  2011 John Wiley & Sons, Ltd. Received: 30 November 2010
Revised: 5 December 2010
Accepted: 5 December 2010

2. 4 EDITORIAL
alobar holoprosencephaly, exomphalos, gastroschisis sonographic measurement of cervical length at 11 to
and megacystis and second, undetectable abnormalities 13 weeks which is inversely related to the likelihood
because sonographic signs are only manifest during the for subsequent spontaneous early delivery (Greco et al.,
second or third trimester of pregnancy, including some 2011). At present there are no other useful biophysical or
brain abnormalities, such as microcephaly, hypoplasia of biochemical markers of spontaneous early delivery (Beta
the cerebellum or vermis, hydrocephalus and agenesis et al., 2011). Future research will determine whether
of the corpus callosum, achondroplasia, echogenic lung early intervention with such measures as prophylactic
lesions, many renal anomalies and bowel obstruction. A use of progesterone or cervical cerclage will be effective
third group includes abnormalities that are potentially in reducing spontaneous preterm delivery.
detectable depending on first the objectives set for such
a scan and consequently the time allocated for the fetal
examination, the expertise of the sonographer and the
quality of the equipment used and second, the pres- PREECLAMPSIA
ence of an easily detectable marker for an underlying
abnormality. Good examples of such markers in the first
trimester include high NT in some fetuses with lethal We have learnt that in preeclampsia, which is a major
skeletal dysplasias (Khalil et al., 2011) and diaphrag- cause of maternal and perinatal morbidity and mor-
matic hernia, high NT and abnormal flow in the ductus tality, both the degree of impaired placentation and
venosus and across the tricuspid valve in major cardiac the incidence of adverse fetal and maternal short-term
defects (Chelemen et al., 2011) and increase in brain and long-term consequences are inversely related to
stem diameter with decrease in the diameter of the fourth the gestational age at the onset of the disease. Con-
ventricle-cisterna magna complex in open spina bifida sequently, in screening for preeclampsia the condition
(Lachmann et al., 2011). should be subdivided according to gestational age at
delivery. Algorithms which combine maternal charac-
teristics, mean arterial pressure, uterine artery Doppler
MISCARRIAGE AND STILLBIRTH and biochemical tests at 11 to 13 weeks could potentially
identify about 90, 80 and 60% of pregnancies that sub-
sequently develop early (before 34 weeks), intermediate
We have learnt that the rates of miscarriage and stillbirth
(34–37 weeks) and late (after 37 weeks) preeclampsia,
after demonstration of a live fetus at 11 to 13 weeks are
for a false positive rate of 5% (Akolekar et al., 2011b).
about 1 and 0.4%, respectively. Increased risk for mis-
Further investigations will determine whether in the
carriage and stillbirth are associated with certain mater-
high-risk group pharmacological interventions, such as
nal characteristics, including increasing maternal age
low-dose aspirin, starting from the first trimester could
and maternal weight, previous miscarriage or stillbirth
improve placentation and reduce the prevalence of the
and African racial origin. Miscarriage and stillbirth are
disease.
also associated with abnormal results of first-trimester
screening for aneuploidies, including increased fetal NT
thickness, reversed a-wave in the fetal ductus veno-
sus and low maternal serum PAPP-A (Akolekar et al.,
2011a). At present there is no useful intervention for GESTATIONAL DIABETES MELLITUS
avoidance of miscarriage and so the use of this algo-
rithm in clinical practice is debatable (van Ravenswaaij We have learnt that in gestational diabetes mellitus
et al., 2011). In contrast, early identification of the group (GDM), which is associated with increased risk of mater-
at high-risk for stillbirth could lead to a reduction of this nal and perinatal short-term and long-term complica-
complication through closer monitoring of fetal growth tions, the performance of traditional screening at the
and wellbeing and appropriate timing of delivery. end of the second trimester by a series of independent
maternal characteristics is poor with a detection rate of
about 60%, at a false positive rate of 30 to 40% (Waugh
PRETERM DELIVERY et al., 2007). Algorithms which combine maternal char-
acteristics and maternal serum levels of adiponectin, an
We have learnt that preterm birth is the leading cause adipocyte-derived polypeptide, and sex hormone binding
of perinatal death and handicap in children and the globulin, a liver-derived glycoprotein, at 11 to 13 weeks
vast majority of mortality and morbidity relates to early could potentially identify about 75% of pregnancies that
delivery before 34 weeks which occurs in about 2% subsequently develop GDM, for a false positive rate of
of singleton pregnancies. In two-thirds of the cases 20% (Nanda et al., 2011). Additionally, the diagnosis of
this is due to spontaneous onset of labor or preterm GDM can be made in the first trimester by appropriate
prelabor rupture of membranes and in the other one- adjustments to the traditional criteria of the oral glucose
third it is iatrogenic, mainly due to preeclampsia. The tolerance test (Plasencia et al., 2011). Future research
patient-specific risk for spontaneous delivery before will determine whether in the high-risk group appro-
34 weeks can be determined by an algorithm combining priate dietary advice and pharmacological interventions,
maternal characteristics and obstetric history (Beta et al., such as metformin, could reduce the incidence of GDM
2011). This a priori risk can be modified by the and associated fetal macrosomia.
Copyright  2011 John Wiley & Sons, Ltd. Prenat Diagn 2011; 31: 3–6.
DOI: 10.1002/pd

3. EDITORIAL 5
SMALL FOR GESTATIONAL AGE FETUSES patient-specific risk based on maternal age is modi-
fied by the sonographic findings and results of bio-
chemical testing both in the first and second trimesters
We have learnt that small for gestational age (SGA)
of pregnancy. The new approach will adhere to the
fetuses may be constitutionally small or growth restricted
teachings of Hippocrates, that we should learn the past
due to impaired placentation, genetic disease or
and research the present to predict the future, and the
environmental damage. In the growth-restricted group
pronouncements of Galileo Galilei, that the language of
the risks of perinatal death and handicap are substantially
God is mathematics and that we should measure every-
increased but these risks can be reduced if the condition
thing that is measurable and make measurable every-
is detected prenatally allowing appropriate monitoring
thing that is not so.
and delivery. Algorithms which combine maternal char-
At 11 to 13 weeks the great majority of women
acteristics, mean arterial pressure, uterine artery Doppler
would be classified as being at low-risk for pregnancy
and the measurement of various placental products in
complications and a small proportion of women would
maternal blood at 11 to 13 weeks could potentially
be selected as being at high-risk (Figure 1). In the
identify, at a false positive rate of 10%, about 75%
low-risk group the number of medical visits can be
of pregnancies without preeclampsia delivering SGA
substantially reduced to perhaps three. One visit at
neonates before 37 weeks and 45% of those delivering at
around 20 weeks will re-evaluate fetal anatomy and
term (Karagiannis et al., 2011). Since the proportion of
growth and reassess risk for such complications as
growth restricted to constitutional small fetuses is higher
preeclampsia and preterm delivery. Another visit at
in the preterm rather than term SGA, it is likely that the
37 weeks will assess maternal and fetal wellbeing and
early biophysical and biochemical markers identify the
determine the best time and method of delivery and this
growth-restricted subgroup among the SGA.
will be repeated at 41 weeks for the few that remain
pregnant at this stage. The high-risk group can have
close surveillance in specialist clinics both in terms of
FETAL MACROSOMIA the investigations to be performed and the personnel
involved in the provision of care. In each of these visits
their risk will be reassessed and they will either remain
We have learnt that fetal macrosomia is associated with high-risk or they will become low-risk in which case the
increased risks for the mother, including cesarean section intensity of their care can be reduced.
and trauma to the birth canal, and for the baby, including Future research will inevitably expand the number of
shoulder dystocia and consequent brachial plexus or conditions that can be identified in early pregnancy and
facial nerve injuries, fractures of the humerus or clavicle define genetic markers of disease that will improve the
and birth asphyxia. Screening for macrosomia (birth accuracy of the a priori risk based on maternal charac-
weight above the 90th centile for gestational age at teristics and medical history. Similarly, new biophysical
delivery) by a combination of maternal characteristics and biochemical markers will be described that may
and obstetric history with fetal NT and maternal serum- replace some of the current ones and modify the value
free ß-hCG and PAPP-A at 11 to 13 weeks could of others. As the years pass, it will become necessary to
potentially identify, at a false positive rate of 10%, re-evaluate and improve the timing and content of each
about 35% of women who deliver macrosomic neonates visit and the likelihood ratios for each test. Early iden-
(Poon et al., 2011). Future research would identify tification of high-risk groups will also stimulate further
new biophysical and biochemical markers which could research that will define the best protocol for their fol-
improve the performance of screening and determine low up and development of strategies for the prevention
the extent to which early identification of the high-risk of disorders of pregnancy or their adverse consequences.
group can improve prenatal surveillance and prevention It is likely that the new challenge for improvement of
of macrosomia itself or the intrapartum complications pregnancy outcome will be met by inverting the pyramid
related to the condition. of prenatal care (Figure 1) to introduce on a large scale
and in a systematic fashion a new model of prenatal care
which will be based on the results of a comprehensive
THE NEW PYRAMID OF CARE assessment at 11 to 13 weeks.
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4. 6 EDITORIAL
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DOI: 10.1002/pd